The overall goal of this study is to elucidate the role of the product on oxygen metabolism superoxide anion, hydroxyl radical, hydrogen peroxide, and singlet oxygen, on the excitation-contraction coupling system of the myocardium. Using both an enzymatic free radical generating system (xanthine-anthine oxidase) and specific subpopulations of leukocytes together with the specific scavengers of oxygen free radicals, we will develop the hypothesis that oxygen free radicals and their products are capable of producing excitation-contraction uncoupling. Specifically, this proposal should result in the following database: 1) The identification of free radical species, specific scavengers and the interaction of free radicals or their products on cardiac sarcoplasmic reticulum, sarcolemma and purified myofibrils. 2) The correlation of free radical generation, either exogenously or endogenously with depressed sarcoplasmic reticulum calcium transport in the intracellular environment (whole heart homogenate) and inhibition with specific free radical scavengers. 3) Using either the isolated papillary muscle system or the skinned cardiac muscle preparation, the demonstration that oxygen free radicals and/or their products can depress mechanical function in cardiac muscle and 4) The development of an in vivo correlation of free radical mediated, leukocyte depression of myocardial function. To do this, a Lewis rat model of inflammatory myocarditis will be developed to test the hypothesis that oxygen free radicals and/or their products can depress myocardial function in vivo. The results of these studies will from the database for the hypothesis that oxygen free radicals and/or their metabolites are capable of mediating intracellular excitation-contraction uncoupling and provide a firmer understanding of the intracellular pathophysiology of such important clinical entities as ischemia/reperfusion injury and leukocytic infiltration of the myocardium.